Amyloid and inflammation: modulation by apoE, gender, air pollution, and drugs. We propose to test novel inflammation-gender-environment interactions on brain amyloid and microbleeds (microhemorrhages) in mouse models for Alzheimer disease (AD) and aging. The highest AD risk group, women apoE4 carriers, is modelled in EFAD mice carrying familial dominant AD genes in combination with human apoE alleles (targeted replacement, ApoE-TR). Female E4FAD mice have the most brain cytokine induction, amyloid peptide (Abeta) accumulation, and microbleeds (pilot data). In humans, cerebral microbleeds are most prevalent in apoE4 carriers, and are associated with higher conversion to clinical AD. Among environmental influence on cognitive aging and AD, urban air pollution is also considered in an experimental model with nano-scale particulate matter (nPM) from an urban traffic air corridor (with Constantinos Sioutas, co-Investigator). The nPM of well-characterized composition are re-aerosolized for controlled exposure of mice. Pilot data show EFAD mice respond with apoE allele specificity. Aim 1 addresses the age schedule of emergence of gender-apoE allele interactions in AD phenotypes during postnatal development and aging. EFAD brains will be studied for inflammatory responses (TNFa, microglia); for APP processing and Abeta deposits; for cerebrovascular amyloid and microbleeds; and for spatial memory (with Christian Pike, co-Investigator). Sex differences will be manipulated by neonatal steroid treatment to test the hypothesis that excess expression of Abeta, in either genetic sex, will drive the level of inflammation and microbleeds. In vitro, EFAD microglia will be studied for apoE-sex interactions on inflammatory gene expression. Aim 2 examines air pollution nPM effects in female EFAD mice by dose and time on accelerating brain inflammation and AD phenotypes. Critical ages of nPM exposure for AD-phenotypes will be examined with findings from Aim 1 for the earliest age showing gender differences in AD-phenotypes. We can only test one sex because nPM treatment doubles the number of variables. We prioritize females in this aim since females are the highest AD risk group. However, in vitro studies of microglia and neurons from adult brains will include both sexes for nPM induced inflammatory and pro-amyloidogenic responses. Aim 3 examines a drug intervention for brain inflammation and microbleeds by a novel gamma secretase modulator to attenuate Abeta synthesis. Drug-treated female EFAD mice will be exposed to chronic nPM and examined for apoE interactions on AD-phenotypes.